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Letters to the Editor |
Department of Molecular, Biosciences, University of Oslo, Oslo, Norway
Address correspondence to the authors at: Department of Molecular Biosciences, University of Oslo, P.O. Box 1041, 0316 Oslo, Norway. Fax 47 22 85 40 61; e-mail janta{at}imbv.uio.no or inger.sandlie{at}imbv.uio.no.
To the Editor:
Dolcini et al.(1) recently reported in this journal a novel splice-site mutation (denoted Bartin) that causes deletion of exon 11 in the human serum albumin (HSA) gene, ALB. In spite of their uncertain relevance to pathophysiology of diseases, differences in HSA sequence have interesting correlations with functional properties and stability. Bisalbuminemia (or alloalbuminemia) is a rare inherited or acquired condition characterized by the occurrence of 2 circulating components that are observed, typically, during routine clinical electrophoresis or in genetic surveys.
Over the past decades several cases of genetic polymorphisms, described in peer-reviewed papers and listed in the analbuminemia register(2), have been characterized as representing site-specific mutations, splice-site mutations, or frame-shift mutations. The deletion reported by Dolcini et al.(1) would give rise to a C-terminally truncated HSA variant of 410 amino acids rather than the 585 amino acids of the wild-type protein, and would almost completely delete domain III of HSA. Furthermore, the authors discuss the impact of the C-terminal end of HSA on in vivo stability. Interestingly, several other reported mutations also generate altered C-terminal HSA variants, resulting from truncation or elongation as well as single mutations in the primary sequence. All identified HSA variants with such alteration are present in serum of heterozygous carrier individuals in the range of 2%–30% of total HSA, a fact that underscores the significance of the C-terminal domain III on stability.
In light of these observations, it is noteworthy that a widely expressed receptor known as the neonatal Fc receptor (FcRn) was recently found to bind HSA(3). This receptor is known to be the major homeostatic regulator of the serum half-life (approximately 20 days) of IgG, as demonstrated in FcRn-deficient mice that show dramatically reduced circulating concentrations of IgG(3). Recently, the same phenomenon was shown to be valid for the long-lived HSA molecule(4). An FcRn-deficient strain degraded albumin twice as fast as the wild-type strain. This finding indicates that FcRn rescues as much albumin from degradation as is produced by the liver. Interestingly, individuals with the rare human syndrome familial hypercatabolic hypoproteinemia show marked decreases of both endogenous IgG and HSA(4). This clinical observation was an unresolved question for decades, until Wani and colleagues(4) elegantly showed that the syndrome is characterized by deficient FcRn expression due to a mutation affecting β2-microglobulin, which together with the so-called heavy chain constitutes the heterodimeric receptor.
Molecular studies reveal that IgG as well as HSA bind FcRn heavy chain in a strictly pH-dependent fashion, binding at acidic pH and releasing at physiological pH(4)(5). The binding sites for the 2 ligands are located distally on the 
2-domain of the heavy chain, a position that allows simultaneous binding, and the binding of IgG does not affect binding of HSA(5). In the proposed regulatory mechanism(3)(4), FcRns, predominantly localized intracellularly in endothelial cells that cover the bloodstream, capture circulating IgG and HSA taken up by fluid-phase pinocytosis, after the ligands enter acidified endosomal compartments. The lower pH herein facilitates binding to FcRn, and the interactions trigger recycling back to the cell surface and release at pH 7.2–7.4. IgG and HSA that escape receptor binding go to lysosomal degradation. An alternative cooperative pathway may be bidirectional transport between the bloodstream and the extravascular space guided by the same pH-dependent mechanism.
In light of the findings of Dolcini et al.(1), it is noteworthy that this FcRn-mediated recycling mechanism is completely dependent on binding to domain III of HSA. Unfortunately, no cocrystal structure or site-directed mutagenesis studies have been performed to investigate the exact interaction site on domain III, but the abnormal HSA variants described lack domain III or have structural alterations in domain III, which is absolutely crucial for the FcRn interaction. These characteristics surely will affect the pH-dependent binding to FcRn and rescue of the protein from degradation. These novel and important findings should be taken into consideration, and they may contribute to reevaluation of existing data and explain clinical observations regarding altered HSA variants.
Acknowledgments
Grant/funding support: This work was supported by grants from the Steering board for Research in Molecular Biology, Biotechnology and Bioinformatics (EMBIO) at the University of Oslo and The Norwegian Cancer Society.
Financial disclosures: None declared.
References
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